Some breast cancer patients have no evidence of metastatic disease at the time of their original diagnosis and treatment, yet ~30-40% of patients will experience recurrent breast cancer months or even years later, suggesting that these disseminated tumors can remain undetected and indolent for extended periods of time2-4. Remarkably little is known about the mechanisms that regulate outgrowth of indolent tumors into overt, clinically relevant disease. We found that certain human breast carcinomas (termed instigators) facilitate growth of otherwise-indolent tumors (termed responders) that had disseminated to distant organs-a process termed systemic instigation. Systemic instigation is mediated by bone marrow- derived cells that incorporate into the microenvironment of the disseminated tumors where they support tumor growth. Importantly, hematopoietic BMCs of mice bearing instigating tumors are rendered pro-tumorigenic in the marrow prior to their mobilizations. Instigating tumor-derived osteopontin (OPN), a cytokine that is elevated in the plasma of patients with metastatic breast cancer and is predictive of poor outcome, is necessary for activating the tumor supportive BMCs5. Bisphosphonates, including zoledronic acid (ZOL), work by inhibiting the activity of bone osteoclasts and many women are treated with bisphosphonates for osteoporosis. Our previous work on systemic instigation provides a possible mechanism by which bisphosphonates might exert both its anti-breast cancer activity as well as its breast cancer prevention ability5. The goal of my proposal is to determine the effect of the bisphosphonate ZOL on the systemic instigation process and elucidate mechanisms by which bisphosphonates affect tumor-supportive bone marrow cells and tumor cell bone colonization. I hypothesize that ZOL's effect on the bone microenvironment prevents breast cancer recurrence by inhibiting the function of pro-tumorigenic bone marrow cells and by inhibiting tumor cell colonization in the bone.